Humans are exposed to chemicals such as brominated flame retardants (BFRs) at unprecedented levels, and a wide variety of health effects are attributed to such exposures. However, the biological mechanisms that link exposures to its consequences remain unknown. An industrial accident in the 1970's exposed over 4000 individuals in rural Michigan to polybrominated biphenyl (PBB), a BFR that was present in the food supply for years prior to detection and management. Health effects are still evident in these individuals and their children. Because this population has been assessed regularly since the exposure, it is an ideal group in which to examine the molecular mechanisms that contribute to susceptibility, vulnerability and health effects. The project goals are to: 1) identify the genetic variants that associate with the rate of PBB elimination over time, 2) identif epigenetic patterns that associate with PBB exposure, 3) integrate genetic and epigenetic datasets and identify complex gene-environment relationships in PBB exposed individuals and 4) evaluate the contribution PBB-associated genetic and epigenetic factors to endocrine-related consequences of exposure. We will leverage data generated as part of past and ongoing studies in the Michigan Polybrominated Biphenyl Cohort and characterize genetic and epigenetic variation in 2 PBB-exposed cohorts, a discovery cohort of 500 subjects exposed through living on or eating food from contaminated farms and a replication cohort of 200 subjects exposed through work at the Michigan Chemical Company that produced PBBs. This research will produce the largest and most comprehensive genetic dataset in subjects exposed to PBBs. We anticipate that this study will provide insight into how genetic variants and the environment interact in relation to PBB exposure and its health effects. We also anticipate the results of this study will be informative for studies of BFRs and other endocrine disrupting compounds with similar chemical properties.